1. Field of the Invention
The invention relates to predictive models for assessing age based on gene expression measurements, to their methods of use, and to computer systems and software for their implementation.
2. Description of the Related Art
The aging process results in a multi-tiered decline in physiological function, ranging from deficiencies at the molecular level, such as increases in DNA damage, to alterations at the cellular level, including changes in metabolism and increased cellular senescence, to system-level changes including a decline in the immune response and increased muscle atrophy. It is generally thought that such changes in function correlate with chronological age, however increasing evidence suggests that such alterations may become manifest in a chronological age-independent fashion. Numerous lines of evidence suggest that a lack of concordance between chronological age and physiological age can exist. A striking example of this is seen in premature aging syndromes such as Hutchinson-Gilford progeria and Werner's syndrome where chronologically young subjects display symptoms often associated with old age such as hair loss, wrinkles, and an increased incidence of heart disease and stroke (for a review see Kudlow et al. Nat. Rev. Mol. Cell Biol. 2007. 8(5):394-404).
As age is an important risk-factor in many diseases including cardiovascular disease, chronologically young subjects that are “physiologically” old may be at increased risk for age-related diseases, and might benefit from early intervention. Currently many routine screenings are recommended in whole or in part based on a subject's chronological age. If it were known that a subject's physiological age is older than his or her chronological age, the subject's physician could start certain routine screenings earlier. This benefits the subject and saves costs associated with aging-related conditions that appear unexpectedly because the subject is “too young” for that condition. For subjects who are “physiologically” young, it may be appropriate to postpone certain screenings or do them less frequently.
Methods for distinguishing physiological age from chronological age in humans have been historically limited to measuring gross physiological changes, such as assessing auditory threshold, near-point vision, and muscle tone. Recent work has suggested that it may be possible to determine physiological age at the molecular level. The ends of chromosomes, called telomeres, shorten by 50-200 base pairs with every cell division; thus cells in chronologically older individuals tend to have shorter telomeres than cells from younger individuals. Studies have shown that subjects with premature myocardial infarctions (“MI”) (age <50 yrs) have significantly shorter telomeres than an age-matched control population, suggesting that telomere length might be a surrogate for physiological age, and that subjects that are physiologically older may have an increased risk for MI (Brouilette et al. Arterioscler. Thromb. Vasc. Biol. 2003. 23(5):842-6).
In addition to telomere length, gene expression profiling has been recently employed as a method to measure age at the molecular level. A number of studies in various tissues (brain, muscle, kidney) have recently demonstrated that changes in gene expression correlate with age (Hong et al. PLoS ONE 3(8):e3024; Zahn et al. PLoS Genet. 2006, 2(7):e115; and Melk et al. Kidney Int. 2005, 68(6):2667-79); however these tissues are not easily obtainable from subjects. Measuring changes in gene expression in circulating blood cells has proven to be a relatively simple, non-invasive method to assess disease status in a number of etiologies including coronary artery disease (Wingrove et al. Circ. Cardiovasc. Genet. 2008, 1:31-38; Aziz et al. Genomic Medicine 2007, 1(3):105-112; Bijnens et al. Arterioscler Thromb Vasc Biol. 2006, 6:1226-35). Lymphocyte senescence can be measured by assessing changes in gene expression; however this study was limited to a subset of circulating cells due to the collection methodology (Hong et al.).
Unmet Clinical and Scientific Need
A major advancement in tailoring medical care to individual subjects would be obtaining information about a subject's “physiological” age through a non-invasive diagnostic test that can guide physicians and other healthcare professionals to choose the types of routine screenings for age-related conditions would be appropriate for the subject.